tbuckley/cabot-search huggingface dataset:
Abstract 1165: Therapeutic targeting of glucocorticoid receptor in ETS rearranged cancer
Authors: Arunachalam Sekar, Nishanth Belugali Nataraj, Yosef Yarden
Journal: Cancer Research (2022)

Abstract The Nuclear receptor Glucocorticoid receptor (GR) acts as a ubiquitous hormone-dependent transcription factor, which regulates many cellular functions. Here, we discovered that some ETS (E-twenty-six) family transcription factors form physical complexes with GR. Two members of the family, FLI1 and ERG exhibited stronger binding with the ligand-activated GR. GR-FLI1 interaction enhance the transcriptional activity of DNA-bound GR. Antagonizing GR or lowering cortisol levels in Ewing sarcoma (ES) animal models, a pediatric bone malignancy driven by EWS-FLI1 fusion, robustly retarded tumor growth, as well as inhibited bone to lung metastasis. These findings prompted us to identify prognostic, GR-regulated gene signature in ES. Because the genomic binding sites of GR in ES are still unknown, using chromatin immunoprecipitation followed by high-throughput DNA sequencing in A673 cells we found previously known and new target genes of GR. By utilizing the protein-fragment complementation assay (PCA), we discovered that GR physically interacts with additional ETS factors. Disruption of this complex is enabled by clinically approved GR antagonist RU486 or newly developed selective GR modulators (i.e., SGRMs without AR or PR cross-reactivity). ETS proteins has been strongly associated with tumor progression and metastasis in several cancers. Taken together, we hypothesised that these mechanisms are also relevant for other ETS rearranged cancers. Results of co-immunoprecipitation analysis confirm the interaction of GR and ERG/ETV4 in ETS-positive prostate cancer cells. In addition, migration and proliferation were reduced when we knocked-down or antagonized GR. It is important noting that the pharmacology of GR is very well developed and some GR-targeting drugs are among the most prescribed medicines. These discoveries will open the way to clinical tests and eventual application of anti- hormone therapy in the discipline of pediatric sarcomas and ETS-rearranged cancers. Citation Format: Arunachalam Sekar, Nishanth Belugali Nataraj, Yosef Yarden. Therapeutic targeting of glucocorticoid receptor in ETS rearranged cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1165.
Abstract 5235: The role of transient single MET inhibition in <i>MET</i>-amplified and <i>EGFR</i>-mutant nonsmall cell lung cancer resistant to EGFR inhibitors
Authors: Youngjoo Lee, Yu-Ra Choi, Eun Hye Kang, Sunshin Kim, SeogYun Park, Ji-Youn Han
Journal: Cancer Research (2022)

Abstract Background: In recent clinical trials for EGFR-mutant lung cancer acquiring MET amplification as resistance to EGFR inhibitor, two-drug combination treatment showed promising anti-tumor activity. However, these combination treatments also resulted in increased toxicity with intolerability. Thus, this study evaluated the possible role of single MET inhibition in these distinct tumors. Methods: Using gefitinib-resistant MET-amplified lung cancer cells (HCC827GR), we tested the sensitivity to single MET inhibitor with various conditions. Supporting preclinical data with cell lines, the matched case reports and drug-sensitivity tests using patient-derived cells were presented. Furthermore, we chronically treated HCC827GR with single MET inhibitor to establish MET inhibitor-resistant cell line (HCC827GR_PR). And then, we explored putative resistance mechanisms of the HCC827GR_PR cells. Results: The HCC827GR cells were partially inhibited by single MET inhibitor regardless of gefitinib-free duration or drug exposure time. Three patients with stage IV MET-amplified and EGFR-mutant lung cancer resistant to EGFR inhibitor showed initially definite response to single crizotinib treatment but their disease progressed within two or three months. The copy number of MET gene in plasma circulating tumor DNA was decreased significantly during crizotinib treatment and not increased even after progression to crizotinib. In their post-crizotinib tumor, MET amplification was disappeared in fluorescence in situ hybridization test. In vitro drug test using patient-derived cells revealed the sensitivity to EGFR inhibitor was recovered after single crizotinib treatment. We established HCC827GR_PR resistant to single MET inhibitor. In the major clones of HCC827GR_PR cells, EGFR signaling pathway was reactivated and gefitinib successfully suppressed their survival. Furthermore, increased MET gene copy number or bypass activation of FGFR1 were observed as resistance mechanism in the minor clones of HCC827GR_PR cells. Conclusions: Single MET inhibitor could be effective but its efficacy could not durable in patients with MET-amplified and EGFR-mutant lung cancer resistant to EGFR inhibitors because these resistant cells might be subclones. A novel combination strategy is needed to get both long-term efficacy and less toxicity in these lung cancer patients. Citation Format: Youngjoo Lee, Yu-Ra Choi, Eun Hye Kang, Sunshin Kim, SeogYun Park, Ji-Youn Han. The role of transient single MET inhibition in MET-amplified and EGFR-mutant nonsmall cell lung cancer resistant to EGFR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5235.
Abstract 936: Developing a sex-biased model for LKB1-mutant lung adenocarcinoma
Authors: Yijian Fan, Rui Jin, Xiuju Liu, Yuan Liu, Chunzi Huang, Mellissa Gilbert-Ross, Adam Marcus, Wei Zhou
Journal: Cancer Research (2022)

Abstract Liver kinase B1 (LKB1) is the third most frequently mutated gene in lung adenocarcinoma (LUAD), and LKB1-mutant lung cancers are resistant to existing targeted therapy or immune checkpoint blockade therapy. In the TCGA-LUAD dataset, LKB1 was found to be more frequently mutated in males than in females even after correcting for potential confounders (male versus female: 22.8% versus 11.3%, p &amp;lt; 6.9x 10-4, FDR = 0.033). Similar trends can be found in all other large LUAD datasets. However, the mechanistic basis of this bias is unknown because the existing mouse models of lung cancers either did not exhibit sex bias or showed female mice being more susceptible to the development of lung cancers. Here, we demonstrate that our lentivirus-inducing Kras/LKB1-mutant genetically engineered mouse model (GEMM) and tail-vein injection syngeneic model exhibit sex bias against the tumor formation in the female host. In our KRASLSL-G12D/LKB1fl/fl/Rosa-Luc GEMM mice, the lung tumor formation was monitored by bioluminescence imaging (BLI) and validated by immunohistochemistry of tumor bearing-lung. The sex bias of time to lung adenocarcinoma formation in males and females was determined by the Kaplan-Meier method. 97% (31/32) male GEMM developed LUAD after the induction, whereas only 58% (15/26) female GEMM developed LUAD (p=0.0001, log-rank). The tail-vein injection method used the WRJ388-AD1 cell line, which was derived from WRJ388. Tumor growth in the chest area was monitored by BLI and evaluated by the mixed-effects model. Sex bias preference for developing lung tumors in the male host reached significance on day 14 post-injection (p=0.0037) and lasted during the study (day 21, p=0.0021). On day 21, with the cutoff as 1x106 p/sec/cm2/sr in lung region, 100% male GEMM formed lung tumor while only 36% female GEMM formed lung tumor after the injection. Collectively, this KRAS/LKB1-mutant lung adenocarcinoma exhibits sex-biased tumor formation and growth, which are consistent with clinical data among LUAD patients. This model will provide researchers with opportunities to understand the mechanistic basis of this sex bias and to develop novel personalized therapies. Citation Format: Yijian Fan, Rui Jin, Xiuju Liu, Yuan Liu, Chunzi Huang, Mellissa Gilbert-Ross, Adam Marcus, Wei Zhou. Developing a sex-biased model for LKB1-mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 936.
Abstract 5484: Preclinical evaluation of CAP-0121 for multidrug resistant cancers
Authors: Michael J. Kelner, Venkata R. Kotamraju
Journal: Cancer Research (2022)

Abstract CAP-0121 is a second generation illudofulvene agent that produces an unusual type of DNA damage and is being developed to treat ovarian cancer by Califia Pharma. CAP-0121 DNA damage, like other illudofulvenes, can only be recognized and repaired by the Transcription-Coupled Repair pathway, and is ignored by the Global Genome Repair Pathway. The first generation illudofulvene, irofulven, displayed significant activity in clinical trials against ovarian, prostate and hepatocellular tumors. While irofulven has proven to be a potent antitumor agent against drug-resistant tumors, its efficacy is limited by hematologic toxicity that reduced the maximum dosage that can be administered to patients. CAP-0121 is as cytotoxic, or even more cytotoxic, than irofulven when tested in the NCI 60 cell line panel. Despite this increased cytotoxicity noted in vitro, CAP-0121 is less toxic to animals and the maximum tolerated dose is approximately 3 times higher than irofulven (mg/kg basis). CAP-0121 also retains activity against multidrug resistant cell lines including MRP1 and MDR1 expressing variants. As a result CAP-0121 is capable of inducing tumor remission in MDR xenograft models that are unresponsive to 35 conventional and experimental agents, and in which irofulven is only capable of slowing the rate of tumor growth. This response of CAP-0121 in drug resistant xenografts is observed at nontoxic doses. Synergistic action is observed when CAP-0121 is administered in combination with traditional drugs used for treating ovarian cancer, including taxanes, platinum agents, and PARP inhibitors. Citation Format: Michael J. Kelner, Venkata R. Kotamraju. Preclinical evaluation of CAP-0121 for multidrug resistant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5484.
Abstract CT526: A Phase 1/2a Study of a PI3Kδγ dual inhibitor ZX-101A in patients with advanced solid tumors
Authors: Xiaoli Qin, Lori Luo, Li Ying-ying, Yin Wang, Shuaijun Sun, Xiaolin Hao, Jinfu Yang
Journal: Cancer Research (2022)

Abstract ZX-101A is a next-generation PI3Kδ/γ dual inhibitor, exerting synergistic effects on PI3Kδ and PI3Kγ-mediated processes through multifaceted mechanisms of actions. Phase 1/2a study, ZX-101A-101 (NCT04504708) is ongoing to assess safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with advanced hematologic malignancies. Furthermore, recent preclinical studies of ZX-101A showed that dual inhibition of PI3Kδ and PI3Kγ restored the immune surveillance to inhibit solid tumor growth. ZX-101A-201 is a phase 1/2a open-label, multiple-dose ascending study to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of once daily oral ZX-101A in 28-day cycles in patients with advanced solid tumors.ZX-101A had minimal effects on solid tumor-derived CT26, 4T1 and A20 cells in in vitro cell proliferation assay. In contrast, ZX-101A inhibited tumor growth when CT26 cells were grafted to wild-type syngeneic mice, while only showed a limited tumor growth inhibition when CT26 tumors grew on T-cell deficient nude mice. Thus, in vivo tumor growth inhibition in wild-type mice was attributed to the enhanced anti-tumor immunity by ZX-101A treatment. Flow cytometry analysis on ex vivo tumor tissues from syngeneic mouse demonstrated that ZX-101A decreased regulatory T cells and increased M1/M2 macrophage polarization in the tumor microenvironment. In A20 syngeneic model, ZX-101A in combination of anti-PD1 antibody achieved 99.7% TGI after 18 days of treatment, while anti-PD1 antibody alone only had TGI at 11.7%. Synergistic inhibitory effect of ZX-101A and anti-PD1 antibody was also observed in LLC, CT26 and humanized MC38 syngeneic mouse models. Safety assessment on the mouse spleen, thymus and colon organs indicated minimal side effects by the treatment of the ZX-101A alone and in combination with anti-PD1. These results suggested ZX-101A as a potential immunotherapeutic agent to treat appropriate solid tumor types. ZX-101A-201 study consists of 2 parts, Dose Escalation and Dose Expansion. Part 1 dose escalation is designed to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of ZX-101A monotherapy in patient with advanced solid tumors. Part 2 dose expansion will evaluate ZX-101A activity in up to three disease-specific cohorts. Inclusion of combination therapy is planned after obtaining the initial clinical assessment of ZX-101A on its safety, tolerability, pharmacokinetics, and pharmacodynamics in patients. Citation Format: Xiaoli Qin, Lori Luo, Li Ying-ying, Yin Wang, Shuaijun Sun, Xiaolin Hao, Jinfu Yang. A Phase 1/2a Study of a PI3Kδγ dual inhibitor ZX-101A in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT526.
Abstract 1576: Chemotherapy induced cellular cannibalism is mediated by phosphoinositide species and clathrin
Authors: Wesley D. Frey, Ashlyn Anderson, Julie Nguyen, Emma Cowles, James Jackson
Journal: Cancer Research (2022)

Abstract Cancer cells can survive chemotherapy and drive lethal relapse if they avoid cell death in conditions of 1) DNA damage and/or mitotic stress caused by treatment; 2) nutrient depletion. We and others have previously shown that the breast cancers most likely to survive chemotherapy are TP53 wild-type, and these are among the most lethal breast cancers. For instance, chemotherapy treated TNBC patients with TP53 wild-type tumors have a median overall survival of 45 months, contrasting with 263 months for TP53 mutant tumors. TP53 wild type cells survive stress by entering a state of arrest and cellular senescence. But to persist in senescence, cells must survive in limited access to vasculature and nutrient sources while also supporting a high metabolic burden that includes production of cytokines and chemokines that drive pro-tumorigenic phenotypes and relapse. We previously showed a novel cannibalism phenotype of chemotherapy induced senescent cells. Engulfment occurred after exposure to different chemotherapy drugs in vitro, in 9 different cell lines, and in vivo in syngeneic mouse mammary tumor models. Engulfed prey cells were processed to the lysosomes of predator cells and broken down. While we showed the phenotype was unrelated to entosis, and senescent cells expressed many phagocytosis/macrophage related genes, the basic mechanisms of the engulfment are unknown. Here, we use biosensors and live cell imaging to delineate the steps of whole cell engulfment in cells that have entered senescence to survive chemotherapy. We show predator cell filamentous actin was localized to the prey cell throughout the process of engulfment. Biosensors to various phosphoinositide (PI) species showed increased concentration and localization of predator PI(4)P and PI(4,5)P2 at the prey cell during early stages of engulfment, followed by a burst of PI(3)P before internalization. PIK3C2B, an enzyme responsible for generating PI(3)P, was required for complete engulfment. Inhibition or knockdown of Clathrin, known to associate with PIK3C2B and PI(4,5)P2, severely impaired engulfment. In sum, these data demonstrate the mechanism of cellular cannibalism used by breast cancer cells to survive chemotherapy. Citation Format: Wesley D. Frey, Ashlyn Anderson, Julie Nguyen, Emma Cowles, James Jackson. Chemotherapy induced cellular cannibalism is mediated by phosphoinositide species and clathrin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1576.
Abstract 357: Characterization of KRas pathway inhibitors in 2D and 3D screening formats
Authors: Katharina Schaich, Daniel Feger, Oliver Siedentopf, Sarah Ulrich, Jan Erik Ehlert
Journal: Cancer Research (2022)

Abstract The KRas/Raf/MEK signalling axis has been identified to play a critical role in the formation of cancer, resulting in several investigational new drugs targeting this pathway. Identification of appropriate drugs is hampered, however, by the assumption that a three-dimensional setting may be required to observe significant inhibitory effects, possibly due to alternate gene expression and protein activity in such a “closer-to-physiology” setting. In order to explore that topic, in the current study we have made use of our 140 cell lines (CL)-2D proliferation panel (3 days incubation) and our 100CL-3D soft agar panel (&amp;gt; 7 days incubation). On these platforms, we have compared inhibitors targeting the KRas/Raf/MEK pathway via either KRas:SOS interaction (e.g. BI3406), the KRas mutation at G12C (e.g. AMG510), or Raf-kinase (e.g. AZ628) and MEK1/2-kinase activity (e.g. AZD6244). It showed that especially the Raf- and MEK kinase inhibitors exhibited significantly enhanced potency in the 3D soft agar setting in the majority of the cell lines tested. The other inhibitors also showed an increased potency under soft agar conditions, however, on clearly fewer cell lines and usually not as strongly. For all kinds of inhibitors tested, the most significant changes in potency were associated with enhanced efficacy as observed by stronger cell death induction. Differences may be attributable to three-dimensional growth, but also to the elongated duration of the soft agar assay. For selected conditions, we addressed this topic by analyzing the inhibitor impact on 3D spheroid growth after shorter incubation times. Our results show that 3D growth analysis either in the soft agar or spheroid setting clearly supports the development of KRas/Raf/MEK pathway inhibitors. Citation Format: Katharina Schaich, Daniel Feger, Oliver Siedentopf, Sarah Ulrich, Jan Erik Ehlert. Characterization of KRas pathway inhibitors in 2D and 3D screening formats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 357.
Abstract CT233: A phase 3, single-arm study of CG0070 in subjects with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG)
Authors: Ed Uchio, Donald Lamm, Neil Shore, Trinity Bivalacqua, Ashish Kamat, Mark Tyson, Paul Anderson, Paola Grandi, James Burke
Journal: Cancer Research (2022)

Abstract IntroductionCG0070 is a serotype 5 adenovirus engineered to express GM-CSF and replicate in cells with mutated or deficient RB, with response rates (RR) of approximately 45% observed in patients with recurrent NMIBC after BCG (J Urol. 2012;188:2391-7; Urol Oncol. 2018;36(10):440-7). This single arm phase 3 study (NCT04452591) was launched to confirm the clinical activity of CG0070 in patients with BCG Unresponsive NMIBC.Methods110 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVe) CG0070 at a dose of 1x1012 vp. CG0070 will be administered as follows: induction weekly x 6 followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 months (m) may receive re-induction with weekly x 6 CG0070. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping at 12 m. Detection of high grade disease within the bladder will be enumerated as recurrence or non-response.ResultsThe primary endpoint of the study is CR at any time on study as assessed by biopsy (directed to cystoscopic abnormalities and mandatory mapping at 12 m), urine cytology, and radiography, as above. Secondary endpoints include CR at 12 m, duration of response, progression free survival, cystectomy free survival and safety. Correlative assessments include changes in the tumor immune microenvironment, systemic immune induction as reflected in the peripheral blood and urine, as well as viral replication and transgene expression. Baseline expression of coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response.ConclusionThe study an ongoing trial, currently enrolling in the United States, Japan, South Korea, Australia, and Taiwan.Refs. Burke JM, Lamm DL, Meng MV, Nemunaitis JJ, Stephenson JJ, Arseneau JC, Aimi J, Lerner S, Yeung AW, Kazarian T, Maslyar DJ, McKiernan JM. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. Citation Format: Ed Uchio, Donald Lamm, Neil Shore, Trinity Bivalacqua, Ashish Kamat, Mark Tyson, Paul Anderson, Paola Grandi, James Burke. A phase 3, single-arm study of CG0070 in subjects with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT233.
Circulating DNA and Liquid Biopsies in the Management of Patients with Cancer
Authors: Simon A. Joosse, Klaus Pantel
Journal: Cancer Research (2022)

Forty-five years ago, Cancer Research published the study by Leon and colleagues in which the authors described the observation of increased levels of cell-free DNA (cfDNA) in the serum of patients with cancer as compared with healthy individuals, with the highest serum levels in patients with metastatic cancer. Most interestingly was the correlation between serum DNA concentrations and therapy outcome: Increased serum DNA levels were associated with poor response to treatment, whereas decreases in DNA levels during treatment appeared to be a sign of better prognosis. Since the discovery of the prognostic value of blood DNA, much research has been focused on the characterization of cfDNA to understand its origins and increase the sensitivity and specificity of using cfDNA as a prognostic and predictive marker in the battle against cancer. Tumor-specific cfDNA markers that were discovered include genetic alterations, chromosomal aberrations, epigenetic modifications, and DNA fragmentation size. In recent years, due to the development of highly sensitive molecular technologies, cfDNA-based assays are now being introduced into the clinic as the so called "liquid biopsy." The advantages of a liquid biopsy over traditional biopsy and imaging have led to the implementation in the clinic for early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. Despite Leon and colleagues' initial skepticism about the potential diagnostic value of serum DNA, cfDNA-based liquid biopsy has become one of the most important tools for personalized cancer treatment. See related article by Leon and colleagues, Cancer Res 1977;37:646-50.